LCZ696 is a novel antihypertensive anti-heart-failure drug developed by Novartis. It is a sacubitril/valsartan complex. The medicine mainly contains two components: Diovan (common name: valsartan) of Novartis and experimental medicine Sacubitril (AHU-377), wherein the Sacubitril can block an action mechanism which threatens two polypeptides in charge of reducing the blood pressure, and the medicine was approved by U.S. Food and Drug Administration on 7 Jul., 2015, and is used for the heart failure patients with a reduced ejection fraction, to reduce the cardiovascular death and heart failure hospitalization risks. The LCZ696 is generally obtained by subjecting Diovan and Sacubitril with a molar ratio of 1:1 to cocrystallization in the mixed solvent of a sodium hydroxide aqueous solution and an organic solvent. LCZ696 consists of Diovan:Sacubitril:Na:H2O=1:1:3:2.5 (molar ratio), and has a chemical formula is as shown in the following formula I.

The Sacubitril gains wide attention as an important constituent of LCZ696. The chemical name of the Sacubitril is 4-{[(2S,4R)-1-(4-biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid, with a Chinese name of: (4-{[(2S,4R)-1-(4-)-5--4--5--2-}-4-), and its chemical formula is as shown in the following formula II:

At present, there are many reports about synthetic methods for Sacubitril, for example, patents WO2008083967, WO2008031567, WO2008031567, WO2010034236, WO2014032627 or the like. Although the synthetic methods for the Sacubitril are relatively mature, due to the influence of the long chain alkyls in molecular structures per se, the crude product of the Sacubitril in the large scale production process is colorless viscous liquid, as a result, the problems that the Sacubitril is hard to be purified and the quality is hard to be controlled are caused.
In the other aspect, in the production process for LCZ696 reported by patent WO2007056546 to Novartis, the crude product of Sacubitril reacts with sodium hydroxide at first to form a sodium salt, then the sodium salt is converted to a calcium salt by ion exchange with calcium chloride to form an isolated solid, the obtained solid is dissociated again with diluted hydrochloric acid, and free acid is regained after the procedures of extraction and concentration. Afterwards, the free Sacubitril acid and valsartan are dissolved in an organic solvent, and the obtained mixture and a sodium hydroxide aqueous solution are subjected to a salt forming reaction and a cocrystallization process to obtain LCZ696. The whole production process needs repeated dissociation and ion exchange, thereby causing a relatively tedious production process flow and the residues of calcium ions which are hard to control.
In addition, patents WO03059345, WO2006086456 and WO2007045663 applied by Novartis discloses the triethanolamine salt and tromethamine salt of Sacubitril. The organic amine salts of the Sacubitril disclosed in these patents are directly used for forming pharmaceutical composition with the valsartan, without preparing LCZ696 by cocrystallization of these organic amine salts after reacting with the valsartan and sodium hydroxide.